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Scientists Reveal Immune System's Role in Bone Loss

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Investigators from the University of California, Los Angeles, shed light on the link between high cholesterol and osteoporosis, identifying a new way that the body's immune cells affect bone loss. High cholesterol leads to increased amounts of oxidized low-density lipoprotein (LDL), which in turn produces excessive RANKL, a chemical normally involved in immune response and bone physiology.

The details appeared in the August 20 issue of Clinical Immunology in a paper called “Oxidized lipids enhance RANKL production by T lymphocytes: Implications for lipid-induced bone loss.”

“We've known that osteoporosis patients have higher cholesterol levels, more severe clogging of the heart arteries, and increased risk of stroke,” points out Rita Effros, Ph.D., professor of pathology at the David Geffen School of Medicine at UCLA. “We also knew that drugs that lower cholesterol reduce bone fractures too. What we didn't understand was why.”

Dr. Effros suspected a clue to the mystery involved cell and tissue damage resulting from exposure of the fatty acids in cholesterol to free radicals. Her team decided to examine how high levels of oxidized LDL affect bone and whether T cells play a role in the process.

Using blood samples from healthy human volunteers, they isolated the participants' T cells and cultured them in a dish. Half the T cells were combined with normal LDL, and the rest with oxidized LDL. The scientists stimulated half the T cells to mimic an immune response and left the other half alone.

The T cells exposed to oxidized LDL displayed a striking response. “Lo and behold, both the resting and the activated T cells started churning out a chemical that stimulates cells whose sole purpose is to destroy bone,” Dr. Effros reports. Called RANKL, the chemical plays a role in immune response and bone loss.

The scientists then repeated the experiment in a mouse model. Half the animals were fed a high-fat diet starting at one month of age, while the control group ate a normal diet. At 11 months, the mice on the high-fat diet showed elevated cholesterol and thinner bones.

When Dr. Effros’ group tested the T cells of the mice on the high-fat diet, they discovered that the cells acted differently than those of the mice on the normal diet. These T cells switched on the gene that produces RANKL. The chemical also appeared in the animals' bloodstream, suggesting that the cellular activity contributed to their bone loss.

“It's normal for our T cells to produce small amounts of RANKL during an immune response,” Dr. Effros explains. “But when RANKL is manufactured for long periods or at the wrong time, it results in excessive bone damage. That's exactly what happened to the mice on the high-fat diet. The animals’ high cholesterol increased their levels of oxidized LDL, which told the T cells to keep generating RANKL.”

The next step will be exploring methods to control T-cell response to oxidized LDL in an effort to develop immune-based approaches to prevent or slow bone loss, Dr. Effros says.

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